IL268584B2 - 15-oxosteroid compound and method for producing same - Google Patents
15-oxosteroid compound and method for producing sameInfo
- Publication number
- IL268584B2 IL268584B2 IL268584A IL26858419A IL268584B2 IL 268584 B2 IL268584 B2 IL 268584B2 IL 268584 A IL268584 A IL 268584A IL 26858419 A IL26858419 A IL 26858419A IL 268584 B2 IL268584 B2 IL 268584B2
- Authority
- IL
- Israel
- Prior art keywords
- group
- compound
- acid
- oxidant
- chain
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 90
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000007800 oxidant agent Substances 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 230000001590 oxidative effect Effects 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 150000002978 peroxides Chemical class 0.000 claims description 7
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 5
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 5
- 150000002497 iodine compounds Chemical class 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 150000004965 peroxy acids Chemical class 0.000 claims description 4
- -1 pregnane steroid compounds Chemical class 0.000 description 39
- 150000003431 steroids Chemical group 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 125000004043 oxo group Chemical group O=* 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 10
- 230000000144 pharmacologic effect Effects 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000002280 anti-androgenic effect Effects 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 229940125797 compound 12 Drugs 0.000 description 5
- 229940126142 compound 16 Drugs 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000575946 Ione Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- UFDULEKOJAEIRI-UHFFFAOYSA-N (2-acetyloxy-3-iodophenyl) acetate Chemical compound CC(=O)OC1=CC=CC(I)=C1OC(C)=O UFDULEKOJAEIRI-UHFFFAOYSA-N 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- LRIUKPUCKCECPT-UHFFFAOYSA-N [hydroxy(phenyl)-$l^{3}-iodanyl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OI(O)C1=CC=CC=C1 LRIUKPUCKCECPT-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- IWOUKMZUPDVPGQ-UHFFFAOYSA-N barium nitrate Chemical compound [Ba+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O IWOUKMZUPDVPGQ-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- RMIBJVUYNZSLSD-UHFFFAOYSA-N bis[(1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-yl)oxy]-diphenyl-$l^{4}-sulfane Chemical compound C=1C=CC=CC=1C(C(F)(F)F)(C(F)(F)F)OS(C=1C=CC=CC=1)(C=1C=CC=CC=1)OC(C(F)(F)F)(C(F)(F)F)C1=CC=CC=C1 RMIBJVUYNZSLSD-UHFFFAOYSA-N 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 2
- YFPCLQKFNXUAAK-UHFFFAOYSA-N cyclopentyl acetate Chemical compound CC(=O)OC1CCCC1 YFPCLQKFNXUAAK-UHFFFAOYSA-N 0.000 description 2
- 238000007256 debromination reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- YDSWCNNOKPMOTP-UHFFFAOYSA-N mellitic acid Chemical compound OC(=O)C1=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C(C(O)=O)=C1C(O)=O YDSWCNNOKPMOTP-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- ZLLOIFNEEWYATC-XMUHMHRVSA-N osaterone Chemical compound C1=C(Cl)C2=CC(=O)OC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 ZLLOIFNEEWYATC-XMUHMHRVSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910001502 inorganic halide Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- BDOLQESNFGCNSC-UHFFFAOYSA-N iodylbenzene Chemical compound O=I(=O)C1=CC=CC=C1 BDOLQESNFGCNSC-UHFFFAOYSA-N 0.000 description 1
- 229910000358 iron sulfate Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- PGJLOGNVZGRMGX-UHFFFAOYSA-L iron(2+);trifluoromethanesulfonate Chemical compound [Fe+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PGJLOGNVZGRMGX-UHFFFAOYSA-L 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940071125 manganese acetate Drugs 0.000 description 1
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229910001960 metal nitrate Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 description 1
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 description 1
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 150000004968 peroxymonosulfuric acids Chemical class 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- GYLIOGDFGLKMOL-UHFFFAOYSA-N trichloromethanol Chemical compound OC(Cl)(Cl)Cl GYLIOGDFGLKMOL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- WZCZNEGTXVXAAS-UHFFFAOYSA-N trifluoromethanol Chemical compound OC(F)(F)F WZCZNEGTXVXAAS-UHFFFAOYSA-N 0.000 description 1
- WRTMQOHKMFDUKX-UHFFFAOYSA-N triiodide Chemical compound I[I-]I WRTMQOHKMFDUKX-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
DESCRIPTION TITLE OF INVENTION -OXOSTEROID COMPOUND AND PROCESS FOR PRODUCING THE SAME TECHNICAL FIELD id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1" id="p-1"
id="p-1"
[0001] The present invention relates to a 15-oxosteroid compound useful as an intermediate for preparing a compound having an oxo group introduced on the 15-position of a steroid skeleton thereof and having a pharmacological activity (for example, an antiandrogenic activity), and a process for producing the 15-oxosteroid compound.
BACKGROUND ART id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2" id="p-2"
id="p-2"
[0002] Pregnane compounds (pregnane steroid compounds) having various physiological activities or pharmacological activities are prepared by introducing various functional groups or active groups to the steroid skeletons. Steroid compounds having antiandrogenic activities are used as agents for treating benign prostatic hyperplasia (prostatomegaly) or other diseases.
However, complicated steps are required to introduce an oxygen-containing functional group to the 15-position of the steroid skeleton. id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3" id="p-3"
id="p-3"
[0003] Japanese Patent No. 2591640 (Patent Document 1) and Chem. Pharm. Bull. 41(5) 870-875 (1993) (Nonpatent Document 1) refer to a 2-oxapregnane compound having acetoxy group introduced on the 15-position of a steroid skeleton thereof and disclose 17a-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,15,20-tr ione (Compound 16 of Chart 2 of the Nonpatent Document 1). Reaction Formula B of the Patent Document 1 and Chart 2 of the Nonpatent Document 1 disclose that (a) 17-hydroxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione (Compound 8) is dehydrated with phosphorus oxychloride to produce 6-chloro-2-oxa-4,6,16-pregnatriene-3,20-dione (Compound 9), (b) the produced 16-dehydro compound is oxidized to produce 6-chloro-17a-hydroxy-2-oxa-4,6,15-pregnatriene-3,20-d ione (Compound 10), (c) the produced 15-dehydro compound is subjected to an addition reaction with N-bromoacetamide (NBA), for giving 15P-acetoxy-16a-bromo-6-chloro-17a-hydroxy-2-oxa-4,6- pregnadiene-3,20-dione (Compound 12: bromo compound). id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4" id="p-4"
id="p-4"
[0004] Unfortunately, these processes, in which acetoxy group is introduced on the 15-position of the steroid skeleton through three steps (the dehydration step, the oxidation step, and the addition step), significantly lower the yield of the pregnane compound. Further, because the addition reaction with N-bromoacetamide introduces a bromine atom on the 16-position of the steroid skeleton, removal of the bromine atom requires debromination of Compound 12. id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5"
id="p-5"
[0005] In particular, more complicated steps are required to obtain the 2-oxapregnane compound (Compound 16) in which the oxo group is introduced on the 15-position of a steroid skeleton thereof. Specifically, it is necessary to debrominate Compound 12 to produce a 17-hydroxy compound (Compound 13) (debromination step), to acetylate the 17-hydroxy compound to produce a 15p,17-diacetoxy compound (Compound 14) (acetylation step), to hydrolyze the diacetoxy compound to produce a 15p-hydroxy compound (hydrolyzation step), and to oxidize the produced 15p-hydroxy compound to form a 15-oxo compound (a 3,15,20-trione compound of Compound 16) (oxidation step). Thus, the 2-oxapregnane compound in which the oxo group is introduced on the 15-position of the steroid skeleton cannot be produced with a high yield by a simple method. id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6"
id="p-6"
[0006] Org. Lett. Vol. 13, No. 16 4308-4311 (2011) (Nonpatent Document 2) discloses oxidation of an unreactive, remote and isolated methylene group of a cycloalkyl or alkyl ester or amide with the use of diacetoxyiodobenzene (DIB) and t-butyl hydroperoxide (TBHP). The Nonpatent Document 2 discloses that cyclopentyl acetate is oxidized to give 3-oxocyclopentyl acetate with a yield of 32% and that cyclohexyl acetate is oxidized to give 3-oxocyclohexyl acetate and 4-oxocyclohexyl acetate with a total yield of 52%.
CITATION LIST PATENT LITERATURE id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7" id="p-7"
id="p-7"
[0007] Patent Document 1: Japanese Patent No. 2591640 (Claims, Reaction Formula B, and Example 3) NONPATENT LITERATURE id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8" id="p-8"
id="p-8"
[0008] Nonpatent Document 1: Chem. Pharm. Bull. 41(5) 870-875 (1993) (Chart 2) Nonpatent Document 2: Org. Lett. Vol. 13, No. 4308-4311 (2011) (Table 2) SUMMARY OF INVENTION TECHNICAL PROBLEM id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9"
id="p-9"
[0009] It is therefore an object of the present invention to provide a compound having an oxo group specifically introduced on the 15-position of a steroid skeleton thereof, and a process for efficiently producing such a compound without complicated steps. id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10"
id="p-10"
[0010] Another object of the present invention is to provide a compound having an oxo group on the 15-position of a steroid skeleton thereof, and a process for producing the compound with a high yield by one or single step (or one-pot reaction). id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11" id="p-11"
id="p-11"
[0011] It is still another object of the present invention to provide a steroid compound useful for preparing a compound having a high pharmacological activity (for example, an antiandrogenic activity), and a process for producing the steroid compound.
SOLUTION TO PROBLEM id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"
id="p-12"
[0012] The inventors of the present invention made intensive studies modification of a steroid skeleton to achieve the above objects and finally found that a compound having a substituent (such as hydroxy group) at the 7-position of a steroid skeleton thereof is specifically oxidized at the 15-position of the steroid skeleton to introduce an oxo group and that use of such a compound having the oxo group introduced on the 15-position of the steroid skeleton as an intermediate enables easy preparation of a compound having a high pharmacological activity (for example, an antiandrogenic activity). The present invention was accomplished based on the above findings. id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13"
id="p-13"
[0013] That is, the present invention provides a -oxosteroid compound represented by the following formula (1). Incidentally, respective positions of the steroid skeleton in the following formula (1) are denoted by positional numbers. id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14"
id="p-14"
[0014] [Chem. 1] id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15"
id="p-15"
[0015] In the formula, R1 to R3 are the same or different and each represent a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group, R4 represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group, or an alkoxycarbonyl group, R5 represents a hydrogen atom, an alkyl group, or an acyl group, R6 represents a hydrogen atom, an alkyl group, an acyl group, or a sulfonyl group, and X represents an oxygen atom (O) or a methylene group (CH2). id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16" id="p-16"
id="p-16"
[0016] R1 may be a halogen atom, R2 to R3 are the same or different and may be an alkyl group or a haloalkyl group, R4 and R5 may be the same or a different acyl group, R may be a hydrogen atom, an acyl group, or a sulfonyl group, and X may be an oxygen atom (O). id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17"
id="p-17"
[0017] The 15-oxosteroid compound represented by the above formula (1) may be a racemate or an optically active substance (or an optical isomer) represented, for example, by the following formula (1a): id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18"
id="p-18"
[0018] [Chem. 2] id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19"
id="p-19"
[0019] wherein R1 to R6 and X have the same meanings as defined above. id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20"
id="p-20"
[0020] The present invention also provides a process for producing the 15-oxosteroid compound. According to this process, the compound represented by the above formula (1) may be prepared by oxidizing a compound represented by the following formula (2) to introduce an oxo group on the 15-position of the steroid skeleton. id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21"
id="p-21"
[0021] [Chem. 3] id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22"
id="p-22"
[0022] In the formulae, R1 to R6 and X have the same meanings as defined above. id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23" id="p-23"
id="p-23"
[0023] For example, the 15-oxosteroid compound represented by the above formula (1) may be produced by oxidizing the compound represented by the formula (2) with an oxidant and a co-oxidant (co-oxidizing agent). id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24" id="p-24"
id="p-24"
[0024] In this process, an optically active compound represented by the formula (2a) may be used as the compound represented by the formula (2) to produce the optical isomer represented by the above formula (1a) while maintaining the configuration thereof. id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25"
id="p-25"
[0025] [Chem. 4] id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26" id="p-26"
id="p-26"
[0026] In the formulae, R1 to R6 and X have the same meanings as defined above. id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27" id="p-27"
id="p-27"
[0027] In this process, the oxidant may contain, for example, a hypervalent iodine compound. The co-oxidant may contain a peroxide and/or a peroxy acid. In the oxidation with the oxidant and the co-oxidant, the reaction may be carried out in the coexistence of a coexisting substance such as an acid, a base, or a salt.
The coexisting substance may positively coexist with the oxidant and the co-oxidant in the reaction, and the coexisting substance may be added to the reaction system in advance before the addition of the oxidant and the co-oxidant to the reaction system or may be added after the addition of the oxidant and the co-oxidant to the reaction system. More specifically, the compound represented by the above formula (1) may be produced by allowing the compound represented by the above formula (2) to react with the hypervalent iodine compound and the peroxide in the presence of a strong acid in a solvent (for example, a solvent inert or inactive to the reaction), then adding an alkali metal carbonate to the reaction system and continuing the reaction.
ADVANTAGEOUS EFFECTS OF INVENTION id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28" id="p-28"
id="p-28"
[0028] According to the present invention, the compound having the oxo group specifically introduced on the -position of the steroid skeleton is simply and efficiently producible through the specific intermediate (the compound (2)) without complicated steps. In particular, the compound having the oxo group on the -position of the steroid skeleton is producible with a high yield by one or single step (or one-pot reaction).
Furthermore, use of the compound having the oxo group introduced on the 15-position of the steroid skeleton as an intermediate enables simple production of a compound having a high pharmacological activity (for example, an antiandrogenic activity) with a reduced or small number of steps.
DESCRIPTION OF EMBODIMENTS id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29"
id="p-29"
[0029] [15-Oxosteroid compound] A compound represented by the above formula (1) is a novel compound and is useful for producing a compound having a high pharmacological activity (for example, an antiandrogenic activity). id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30"
id="p-30"
[0030] In the above formula (1), a halogen atom represented by each of R1 to R4 may include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The halogen atom may practically be a fluorine atom, a chlorine atom, or a bromine atom, particularly a fluorine atom or a chlorine atom. id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31"
id="p-31"
[0031] As examples of an alkyl group represented by each of R1 to R6, there may be mentioned a straight-chain or branched-chain C1-12alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, hexyl group, or octyl group. The alkyl group is usually a straight-chain or branched-chain C1-6alkyl group, preferably a straight-chain or branched-chain C1-4alkyl group, and more preferably a straight-chain or branched-chain C1-3alkyl group. id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32" id="p-32"
id="p-32"
[0032] An alkoxy group represented by each of R1 to R4 may include an alkoxy group corresponding to the alkyl group, for example, a straight-chain or branched-chain C1-12alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, or t-butoxy group. The alkoxy group is usually a straight-chain or branched-chain C1-6alkoxy group, preferably a straight-chain or branched-chain C1-4alkoxy group, and more preferably a straight-chain or branched-chain C1-3alkoxy group. id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33"
id="p-33"
[0033] As examples of a halogen atom in a haloalkyl group and a haloalkoxy group represented by each of R1 to R3, there may be mentioned the halogen atom exemplified in the above. The halogen atom is usually a fluorine atom, a chlorine atom, or a bromine atom, particularly a fluorine atom or a chlorine atom. Examples of the haloalkyl group may include a straight-chain or branched-chain haloC1-12alkyl group such as chloromethyl group, trichloromethyl group, fluoromethyl group, trifluoromethyl group, 2,2,2-trichloroethyl group, perchloroethyl group, 2,2,2-trifluoroethyl group, perfluoroethyl group, or perfluoroisopropyl group. The haloalkyl group is usually a straight-chain or branched-chain haloC1-6alkyl group such as trichloromethyl group or trifluoromethyl group, preferably a haloC1-4alkyl group, and more preferably a haloC1-3alkyl group. id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34" id="p-34"
id="p-34"
[0034] As examples of the haloalkoxy group represented by each of R1 to R3, there may be mentioned a haloalkoxy group corresponding to the haloalkyl group, for example, a straight-chain or branched-chain haloC1-12alkoxy group such as trichloromethoxy group, trifluoromethoxy group, perchloroethoxy group, perfluoroethoxy group, or perfluoropropoxy group. The haloalkoxy group is usually a straight-chain or branched-chain haloC1-6alkoxy group such as trichloromethoxy group or trifluoromethoxy group, preferably a haloC1-4alkoxy group, and more preferably a haloC1-3alkoxy group. id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35"
id="p-35"
[0035] An acyl group represented by each of R4, R5, and R6 may include, for example, formyl group; a straight-chain or branched-chain C1-12alkyl-carbonyl group such as acetyl group, propionyl group, butyryl group, isobutyryl group, t-butyryl group, pentanoyl group (valeryl group), or hexanoyl group; a C3-10cycloalkyl-carbonyl group such as cyclohexylcarbonyl group; a C6-12aryl-carbonyl group which may have a substituent (such as a C1-4alkyl group, a halogen atom, or a nitro group), e.g., benzoyl group, toluoyl group, or naphthoyl group; and a heterocyclic acyl group having at least one hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom (such as furoyl group, nicotinoyl group, or isonicotinoyl group).
The acyl group is usually an alkylcarbonyl group, for example, a straight-chain or branched-chain C1-6alkyl-carbonyl group, preferably a C2-4alkyl-carbonyl group, and more preferably a C2-3alkyl-carbonyl group. id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36"
id="p-36"
[0036] An alkoxycarbonyl group represented by R4 may include, for example, a straight-chain or branched-chain C1-12alkoxy-carbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, or hexyloxycarbonyl group. The alkoxycarbonyl group is usually a straight-chain or branched-chain C1-6alkoxy-carbonyl group, preferably a C1-4alkoxy-carbonyl group, and more preferably a C1-3alkoxy-carbonyl group. id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37"
id="p-37"
[0037] As examples of a sulfonyl group represented by R6, there may be mentioned a C1-6alkanesulfonyl group such as methanesulfonyl group, ethanesulfonyl group, or t-butanesulfonyl group, and a C6-12arenesulfonyl group which may have a substituent (such as a C1-4alkyl group, a halogen atom, or a nitro group), e.g., benzenesulfonyl group or toluenesulfonyl group. id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38" id="p-38"
id="p-38"
[0038] X may be either an oxygen atom (O) or a methylene group (CH2). id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39"
id="p-39"
[0039] In the 15-oxosteroid compound represented by the above formula (1), R1 may practically be a halogen atom (e.g., a fluorine atom or a chlorine atom) and R2 and R3 may practically be the same or different and each represent an alkyl group (e.g., a straight-chain or branched-chain C1-4alkyl group) or a haloalkyl group (e.g., a straight-chain or branched-chain C1-4alkoxy group).
Moreover, in practical cases, R4 and R5 may be the same or a different acyl group, for example, an alkylcarbonyl group (e.g., a straight-chain or branched-chain C1-4alkyl-carbonyl group), R6 may be a hydrogen atom or an acyl group (e.g., an alkylcarbonyl group such as a straight-chain or branched-chain C1-4alkyl-carbonyl group), and X may be an oxygen atom (O). id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40"
id="p-40"
[0040] The 15-oxosteroid compound represented by the formula (1) may be a racemate or may be an optical isomer.
A preferred 15-oxosteroid compound includes an optically active substance (an optical isomer) represented by the following formula (1a): id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41" id="p-41"
id="p-41"
[0041] [Chem. 5] R1 id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42"
id="p-42"
[0042] wherein R1 to R6 and X have the same meanings as defined above. id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43"
id="p-43"
[0043] The 15-oxosteroid compound represented by the above formula (1) or (1a) may have a physiological activity or a pharmacological activity. Use of the 15-oxosteroid compound of the present invention as an intermediate provides a compound having a physiological activity or a pharmacological activity simply with a high yield. For example, in the formula (1) or (1a), the group -OR6 on the 7-position of the steroid skeleton may be eliminated with a usual method to prepare a compound which is represented by the following formula (3) or (3a) and which is described in the Nonpatent Document 1 (such as Compound 16): id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44" id="p-44"
id="p-44"
[0044] [Chem. 6] id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45" id="p-45"
id="p-45"
[0045] wherein R1 to R5 and X have the same meanings as defined above. id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46"
id="p-46"
[0046] Concretely, for example, the compound represented by the above formula (1) in which the group -OR6 is hydroxyl group may be, for example, subjected to a dehydration reaction in the presence of an eliminating agent (such as thionyl chloride, phosphorus oxychloride, or Martin sulfurane) to prepare the compound represented by the formula (3) or (3a). id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47" id="p-47"
id="p-47"
[0047] Moreover, in a case where the compound has an alkoxy group as the group -OR6, the alkoxy group may be converted into hydroxyl group with an action of an acid (for example, sulfuric acid, hydriodic acid, and hydrobromic acid) and subjected to the same dehydration reaction as above, thus preparing the compound represented by the formula (3) or (3a). id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48"
id="p-48"
[0048] In a case where the compound has an acyloxy group (such as acetyloxy group) or a sulfonyloxy group as the group -OR6, the group -OR6 may be eliminated (or liberated) by subjecting the compound to an elimination reaction in the presence of a basic solvent or a base (e.g., an alkali metal hydroxide, an alkali metal carbonate, and an alkali metal acetate such as sodium acetate or potassium acetate). id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49"
id="p-49"
[0049] [Process for producing 15-oxosteroid compound] The 15-oxosteroid compound represented by the above formula (1) may be prepared by oxidizing the compound represented by the following formula (2). Even in a case where the compound represented by the following formula (2a) is oxidized, the optically active substance represented by the formula (1a) may be prepared while maintaining the configuration (steric configuration). id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50"
id="p-50"
[0050] [Chem. 7] id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51"
id="p-51"
[0051] In the formulae, R1 to R6 and X have the same meanings as defined above. id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52"
id="p-52"
[0052] The compound represented by the above formula (2) or (2a) is a known substance. For example, the compound in which R6 is hydroxyl group and the compound in which R6 is acetyl group are described as Compound 11 and Compound 13 in Chart 2 of Chem. Pharm. Bull. 40(4), 935-9 (1992). Thus, the compound represented by the formula (2) or (2a) may be prepared in accordance with the method described in this document, or if possible, may be commercially available one. id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53"
id="p-53"
[0053] The oxidation reaction may be carried out using an oxidant and a co-oxidant. id="p-54" id="p-54" id="p-54" id="p-54" id="p-54" id="p-54" id="p-54" id="p-54" id="p-54" id="p-54"
id="p-54"
[0054] Examples of the oxidant may include a hypervalent iodine compound (an organic periodide or a catalyst), e.g., iodosobenzene diacetate (or iodobenzene diacetate), [bis(trifluoroacetoxy)iodo]benzene, (di-tert-butylcarbonyloxyiodo)benzene, (hydroxytosyloxyiodo)benzene (Koser reagent), (difluoroiodo)toluene, 2-iodoxybenzoic acid, 2-iodoxybenzenesulfonic acid, iodosylbenzene, and iodoxybenzene. Moreover, the oxidant may be an active species or the above-mentioned catalyst generated from an organoiodine compound in the reaction system. These oxidants may be used alone or in combination. A preferred oxidant includes iodobenzene diacetate, [bis(trifluoroacetoxy)iodo]benzene, or other oxidants. id="p-55" id="p-55" id="p-55" id="p-55" id="p-55" id="p-55" id="p-55" id="p-55" id="p-55" id="p-55"
id="p-55"
[0055] The amount of the oxidant may be, for example, about 0.1 to 50 mol, preferably about 0.5 to 25 mol (e.g., about 1 to 20 mol), and more preferably about 2 to 10 mol (e.g., about 3 to 8 mol), relative to 1 mol of the compound represented by the formula (2). id="p-56" id="p-56" id="p-56" id="p-56" id="p-56" id="p-56" id="p-56" id="p-56" id="p-56" id="p-56"
id="p-56"
[0056] The co-oxidant may include a peroxide, for example, hydrogen peroxide, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, tert-amyl hydroperoxide, di-tert-amyl peroxide, cumene hydroperoxide, dicumyl peroxide, tert-butyl cumyl peroxide, tert-butyl peroxypyvalate, benzoyl peroxide, lauroyl peroxide, and ethylbenzene hydroperoxide; a peroxy acid, for example, peracetic acid, trichloroperacetic acid, trifluoroperacetic acid, perbenzoic acid, and p-nitroperbenzoic acid; and Oxone, for example, a potassium salt of persulfuric acid (potassium peroxymonosulfate). These co-oxidants may also be used alone or in combination. As the co-oxidant, practically used may be the peroxide or the peroxy acid, for example, the peroxide such as tert-butyl hydroperoxide (TBHP). id="p-57" id="p-57" id="p-57" id="p-57" id="p-57" id="p-57" id="p-57" id="p-57" id="p-57" id="p-57"
id="p-57"
[0057] The amount of the co-oxidant may be, for example, about 0.1 to 100 mol (e.g., about 1 to 50 mol), preferably about 1.5 to 30 mol, and more preferably about 5 to mol (e.g., about 5 to 15 mol), relative to 1 mol of the compound represented by the formula (2). id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58"
id="p-58"
[0058] The oxidation reaction may be carried out in the coexistence of a coexisting substance (for example, an acid, a base, and a salt). The reaction in the presence of such a coexisting substance may improve the yield of an object compound. id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59"
id="p-59"
[0059] The acid may be any of an inorganic acid, an organic acid, and a Lewis acid. As examples of the inorganic acid, there may be mentioned a mineral acid such as hydrochloric acid, hydrogen chloride, hydrobromic acid, hydrogen bromide, sulfuric acid, sulfurous acid, fuming sulfuric acid, nitric acid, fuming nitric acid, nitrous acid, phosphoric acid, boric acid, hydrofluoboric acid, carbonic acid, or silicic acid. id="p-60" id="p-60" id="p-60" id="p-60" id="p-60" id="p-60" id="p-60" id="p-60" id="p-60" id="p-60"
id="p-60"
[0060] The organic acid may include an organic carboxylic acid compound and a sulfonic acid compound. As examples of the organic carboxylic acid compound, there may be mentioned an alkanecarboxylic acid which may have a halogen atom, such as formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid, or lauric acid; a hydroxycarboxylic acid such as glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; a cycloalkanecarboxylic acid such as cyclohexanecarboxylic acid; a dicarboxylic acid or polycarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, fumaric acid, maleic acid, or aconitic acid; and an arenecarboxylic acid or polycarboxylic acid such as benzoic acid, phthalic acid, mellitic acid, or cinnamic acid. Examples of the sulfonic acid compound may include an alkanesulfonic acid which may have a halogen atom, such as methanesulfonic acid or trifluoromethanesulfonic acid; an arenesulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid; and a cycloalkanesulfonic acid which may be a bridged cyclic compound, such as camphorsulfonic acid. id="p-61" id="p-61" id="p-61" id="p-61" id="p-61" id="p-61" id="p-61" id="p-61" id="p-61" id="p-61"
id="p-61"
[0061] The Lewis acid may include, for example, scandium trifluoromethanesulfonate and iron trifluoromethanesulfonate. id="p-62" id="p-62" id="p-62" id="p-62" id="p-62" id="p-62" id="p-62" id="p-62" id="p-62" id="p-62"
id="p-62"
[0062] These acids may be used alone or in combination.
A preferred acid includes a strong acid, for example, an inorganic acid such as sulfuric acid, a haloalkanecarboxylic acid such as trifluoroacetic acid, and sulfonic acid. Practically used may be sulfuric acid. id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63"
id="p-63"
[0063] The amount of the acid (or acid catalyst) is not particularly limited to a specific one and may be, for example, about 0.0001 to 0.1 equivalents, preferably about 0.0005 to 0.05 equivalents, and more preferably 0.001 to 0.01 equivalents, relative to 1 mol of the compound represented by the formula (2). id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64"
id="p-64"
[0064] The base may include an inorganic base and an organic base. As examples of the inorganic base, there may be mentioned an alkali metal carbonate or hydrogen carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate; an alkali metal alkoxide such as t-butoxypotassium; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkaline earth metal hydroxide such as calcium hydroxide or barium hydroxide; a polyvalent metal hydroxide such as aluminum hydroxide; and an alkylated alkali metal such as n-butyllithium. Examples of the organic base may include a tertiary amine such as pyridine or triethylamine. These bases or salts may also be used alone or in combination. As the base, the alkali metal carbonate, for example, potassium carbonate, may practically be used. id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65"
id="p-65"
[0065] The salt (including an inorganic halide) may include an inorganic salt, an organic acid salt, and a transition metal complex (or complex salt). As examples of the inorganic salt, there may be mentioned an inorganic acid salt, for example, a metal halide, e.g., an alkali metal halide such as sodium chloride, potassium chloride, or potassium bromide, and an alkaline earth metal halide such as calcium chloride; an alkali metal sulfate such as sodium sulfate or potassium sulfate, an alkaline earth metal sulfate such as magnesium sulfate, calcium sulfate, or barium sulfate, and a polyvalent metal sulfate such as aluminum sulfate, copper sulfate, iron sulfate, nickel sulfate, or cobalt sulfate; an alkali metal nitrate such as sodium nitrate or potassium nitrate, an alkaline earth metal nitrate such as magnesium nitrate or barium nitrate, and a polyvalent metal nitrate such as nickel nitrate.
As examples of the organic acid salt, there may be mentioned a carboxylic acid salt (e.g., an acetate) such as magnesium acetate or manganese acetate. The transition metal complex (or complex salt) may include a cobalt complex. These salts may be a neutral salt. id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66"
id="p-66"
[0066] The amount of the base or salt may be, for example, about 0.1 to 15 mol, preferably about 0.5 to 10 mol, and more preferably about 1 to 7 mol (e.g., about 2 to 6 mol), relative to 1 mol of the compound represented by the formula (2). id="p-67" id="p-67" id="p-67" id="p-67" id="p-67" id="p-67" id="p-67" id="p-67" id="p-67" id="p-67"
id="p-67"
[0067] The coexisting substance may positively coexist with the oxidant and the co-oxidant in the reaction, and the timing for the addition of the coexisting substance to the reaction system is not particularly limited to specific manner. The coexisting substance may be added to the reaction system in advance before the addition of the oxidant and the co-oxidant or may be added after the addition of the oxidant and the co-oxidant. id="p-68" id="p-68" id="p-68" id="p-68" id="p-68" id="p-68" id="p-68" id="p-68" id="p-68" id="p-68"
id="p-68"
[0068] The reaction may be carried out in a solvent. The solvent may include various solvents (particularly, a solvent inert or inactive to the reaction), for example, an ether-series solvent (e.g., a chain ether compound such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, or cyclopentyl methyl ether, and a cyclic ether compound such as tetrahydrofuran or dioxane), a hydrocarbon-series solvent [e.g., an aromatic hydrocarbon-series solvent (such as benzene, toluene, xylene, or chlorobenzene) and an aliphatic hydrocarbon-series solvent (such as pentane, hexane, heptane, or octane)], an amide-series solvent (such as N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone), an alcoholic solvent (e.g., an alkanol such as methanol, trichloromethanol, trifluoromethanol, ethanol, trifluoroethanol, trichloroethanol, n-propanol, 2-propanol, n-butanol, s-butanol, t-butanol, pentanol, or hexanol; a cycloalkanol such as cyclopropanol, cyclobutanol, cyclopentanol, or cyclohexanol; a diol such as ethylene glycol, 1,3-propanediol, 1,4-butanediol, or 1,5-pentanediol; and a polyhydric alcohol such as glycerin), an ester-series solvent (such as methyl acetate, ethyl acetate, or isopropyl acetate), a nitrile-series solvent (such as acetonitrile, propionitrile, or benzonitrile), a nitroalkane-series solvent (nitromethane, nitroethane), and a basic nitrogen-containing solvent (a tertiary amine, for example, a trialkylamine such as triethylamine, and a cyclic amine such as pyridine or quinoline). These solvents may be used alone or as a mixed solvent. A preferred solvent may be a mixed solvent containing at least two kinds of organic solvents, for example, a mixed solvent of 2,2,2-trifluoroethanol and chlorobenzene. id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69"
id="p-69"
[0069] The reaction may be carried out at a temperature of about -50°C to 50°C (for example, about -30°C to 0°C), and the atmosphere may be, for example, an oxygen-containing atmosphere (e.g., in air) or an inert atmosphere. Moreover, the reaction may usually be carried out while continuously or intermittently adding a strong oxidant to the reaction system. id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70"
id="p-70"
[0070] The reaction in the presence of the base or the salt may also be carried out at a temperature of about -50 °C to 50°C (for example, about -30°C to 0°C) as described above. id="p-71" id="p-71" id="p-71" id="p-71" id="p-71" id="p-71" id="p-71" id="p-71" id="p-71" id="p-71"
id="p-71"
[0071] After the completion of the reaction, the reaction mixture may be separated and purified by a usual separation and purification means, for example, a method such as solvent extraction, neutralization, concentration, washing, crystallization, or recrystallization, to give an object compound with a high yield. id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72"
id="p-72"
[0072] Incidentally, the Nonpatent Document 2 discloses the oxidation reaction of a substrate such as acetyloxycyclopentane with the oxidant and the co-oxidant in the presence of the acid. However, in the Nonpatent Document 2, an object compound is only obtained with a low yield. In contrast, according to the present invention, oxidizing the compound having the specific substituent at the 7-position of the steroid skeleton can selectively or specifically introduce an oxo group on the -position of the steroid skeleton, while maintaining an optical activity for an optically active substance, and can produce an object compound with high conversion and selectivity.
EXAMPLES id="p-73" id="p-73" id="p-73" id="p-73" id="p-73" id="p-73" id="p-73" id="p-73" id="p-73" id="p-73"
id="p-73"
[0073] The following examples are intended to describe this invention in further detail and should by no means be interpreted as defining the scope of the invention. id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74"
id="p-74"
[0074] Example 1 id="p-75" id="p-75" id="p-75" id="p-75" id="p-75" id="p-75" id="p-75" id="p-75" id="p-75" id="p-75"
id="p-75"
[0075] [Chem. 8] id="p-76" id="p-76" id="p-76" id="p-76" id="p-76" id="p-76" id="p-76" id="p-76" id="p-76" id="p-76"
id="p-76"
[0076] The above compound (2a-1) was subjected to an oxidation reaction to give the above compound (1a-1). id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77"
id="p-77"
[0077] Specifically, a mixture of 6p-chloro-7a-hydroxy-3,20-dioxo-2-oxapregn-4-en-17-yl acetate (the above compound (2a-1), 90.0 g), 2,2,2-trifluoroethanol (162 mL), and chlorobenzene (2.520 L) was cooled to -24 ±2°C, and iodobenzene diacetate (409.2 g) and sulfuric acid (0.3 mL) was added thereto.
To the resultant mixture was added dropwise a tert-butyl hydroperoxide aqueous solution (301 mL) having a concentration of 70% at the same temperature, and the resulting mixture was stirred for 40 minutes while maintaining the above temperature. To the reaction mixture was added potassium carbonate (131.8 g) while maintaining the above temperature, and the resulting mixture was stirred for 44 hours at the same temperature. id="p-78" id="p-78" id="p-78" id="p-78" id="p-78" id="p-78" id="p-78" id="p-78" id="p-78" id="p-78"
id="p-78"
[0078] The resulting reaction mixture was poured into a cooled solution containing sodium pyrosulfite (90.0 g) and sodium chloride (540.0 g) in water (1.53 L) and having a temperature of 2°C, the reaction vessel was washed with ethyl acetate (720 mL), and the combined mixture was stirred at a room temperature. The resulting mixture was separated into an upper layer (or phase) and a lower layer (or phase), and the lower layer was re-extracted with ethyl acetate (360 mL). These upper layers were combined, and the combined upper layers were washed with a solution containing sodium dihydrogen phosphate (180.0 g) and sodium chloride (270.0 g) in water (1.8 L) and having a pH of 7.5 adjusted with sodium hydroxide having a concentration of 30% by weight. Then, the resulting organic layer was washed with a solution containing sodium chloride (225.0 g) in water (720 ml), and the washed layer was concentrated at a temperature of not higher than 50°C under a reduced pressure until the remaining amount was reduced to about 2.52 L. The concentrate was stirred vigorously, and heptane (5.4 L) was added thereto. The resulting mixture was stirred at 18°C overnight. The precipitated crystal was collected by filtration and was washed with heptane (315 mL). The resulting crude crystal was dissolved in a mixture of acetone (378 mL) and water (38 mL), and water (1.44 L) was added thereto with vigorous stirring. The resulting suspension was concentrated at a temperature of not higher than 50°C under a reduced pressure until the remaining amount was reduced to about 1.44 L. The suspension was stirred for 75 minutes at 10°C, and the crystal was collected by filtration and was washed with water (270 mL). The resulting crystal was dried at 50°C for 10 hours to give 268584/2 6p-chloro-7a-hydroxy-3,15,20-trioxo-2-oxapregn-4-en- 7-yl acetate (the above compound (1a-1), 65.2 g (70.1% yield)). The compound was purified by column chromatography (elution solvent n-hexane:ethyl acetate = 1:1 to 1:2) to obtain an analytical sample. id="p-79" id="p-79" id="p-79" id="p-79" id="p-79" id="p-79" id="p-79" id="p-79" id="p-79" id="p-79"
id="p-79"
[0079] NMR: 1H-NMR (400 MHz, CDCl3)d: 0.83 (3H, s), 1.48 (3H, s), 1.49-1.71 (4H, m), 2.12-2.22 (1H, m), 2.14 (3H,`s), 2.19 (3H, s), 2.46-2.56 (2H, m), 2.78 (1H, d, J = 11.
Hz), 3.49 (1H, d, J = 20.0 Hz), 4.09, 4.22 (2H, ABq, J = 10.8 Hz), 4.47 (1H, d, J = 2.9 Hz), 5.04 (1H, brs), 6.01 (1H, s) MASS: m/z 438 (M+) Example 2 id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80"
id="p-80"
[0080] [Chem. 9] id="p-81" id="p-81" id="p-81" id="p-81" id="p-81" id="p-81" id="p-81" id="p-81" id="p-81" id="p-81"
id="p-81"
[0081] The above compound (1a-1) was subjected to a dehydration reaction to give the above compound (3a-1). id="p-82" id="p-82" id="p-82" id="p-82" id="p-82" id="p-82" id="p-82" id="p-82" id="p-82" id="p-82"
id="p-82"
[0082] Specifically, a mixture of 6P-chloro-7a-hydroxy-3,15,20-trioxo-2-oxapregn-4-en- 7-yl acetate (the above compound (1a-1), 9.35 g) and dichloromethane (240 ml) was cooled with ice under an argon atmosphere, and to the mixture was added dropwise a solution of Martin sulfurane (bis[a,a-bis (trifluoromethyl)benzenemethanolato]diphenylsulfur) (20 g) in dichloromethane (110 ml). The resulting mixture was stirred at a room temperature overnight. id="p-83" id="p-83" id="p-83" id="p-83" id="p-83" id="p-83" id="p-83" id="p-83" id="p-83" id="p-83"
id="p-83"
[0083] The reaction mixture was concentrated under a reduced pressure. The resulting concentrate was purified by column chromatography (elution solvent n-hexane:ethyl acetate = 1:1 to 2:3) to give 17a-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,15,20-tr ione (the above compound (3a-1), 5.8 g (64.7% yield)). id="p-84" id="p-84" id="p-84" id="p-84" id="p-84" id="p-84" id="p-84" id="p-84" id="p-84" id="p-84"
id="p-84"
[0084] Comparative Example In accordance with Chart 2 and the conditions of each reaction step described in the Nonpatent Document 1, Compound 12 was prepared from Compound 8 as a starting material via Compound 9 and Compound 10. The yield was 7.8%. Furthermore, Compound 16 was prepared from Compound 12 via Compound 13, Compound 14, and Compound 15a. The yield was 7.7%.
INDUSTRIAL APPLICABILITY id="p-85" id="p-85" id="p-85" id="p-85" id="p-85" id="p-85" id="p-85" id="p-85" id="p-85" id="p-85"
id="p-85"
[0085] The 15-oxosteroid compound of the present invention represented by the formula (1) can produce the compound having the oxo group on the 15-position of the steroid skeleton by the elimination of the group -OR6.
Thus, the compound of the present invention is useful as an intermediate for producing the compound having a high pharmacological activity (for example, an antiandrogenic activity).
Claims (5)
1. / CLAIMS [Claim 1] A 15-oxosteroid compound represented by the following formula (1a): [Chem. 1] wherein R to R are the same or different and each represent a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group, R represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group, or an alkoxycarbonyl group, R represents a hydrogen atom, an alkyl group, or an acyl group, R represents a hydrogen atom, an alkyl group, an acyl group, or a sulfonyl group, and X represents an oxygen atom (O) or a methylene group (CH).
2. [Claim 2] The 15-oxosteroid compound according to claim 1, wherein R is a halogen atom, R and R are the same or different and are an alkyl group or a haloalkyl group, R and R are the same or a different acyl group, R is a hydrogen atom, an acyl group, or a sulfonyl group, and X is an oxygen atom.
3. [Claim 3] A process for producing a 15-oxosteroid compound recited in claim 1 or 2, the process comprising oxidizing a compound represented by the following formula (2a): [Chem. 2] wherein R to R and X have the same meanings as defined in claim 1, with an oxidant and a co-oxidant, wherein the oxidant contains a hypervalent iodine compound, wherein the co-oxidant contains a peroxide and/or a peroxy acid. 268584/ .
4. [Claim 4] The process according to claim 3, wherein a coexisting substance is added in the oxidation with the oxidant and the co-oxidant.
5. [Claim 5] The process according to claim 3 or 4, wherein the compound is allowed to react with the hypervalent iodine compound and the peroxide in the presence of a strong acid in a solvent, then an alkali metal carbonate is added to the reaction system and the reaction is continued. 10
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017023569A JP6892278B2 (en) | 2017-02-10 | 2017-02-10 | 15-oxosteroid compound and its production method |
| PCT/JP2018/004295 WO2018147345A1 (en) | 2017-02-10 | 2018-02-08 | 15-oxosteroid compound and method for producing same |
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| Publication Number | Publication Date |
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| IL268584A IL268584A (en) | 2019-09-26 |
| IL268584B1 IL268584B1 (en) | 2023-08-01 |
| IL268584B2 true IL268584B2 (en) | 2023-12-01 |
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| IL268584A IL268584B2 (en) | 2017-02-10 | 2018-02-08 | 15-oxosteroid compound and method for producing same |
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| Country | Link |
|---|---|
| US (1) | US10815268B2 (en) |
| EP (1) | EP3581577B1 (en) |
| JP (1) | JP6892278B2 (en) |
| KR (1) | KR102467727B1 (en) |
| CN (1) | CN110267967B (en) |
| ES (1) | ES2968278T3 (en) |
| IL (1) | IL268584B2 (en) |
| MX (1) | MX389873B (en) |
| WO (1) | WO2018147345A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2823170A (en) * | 1955-05-11 | 1958-02-11 | Searle & Co | Process for the oxygenation of steroids with nigrospora |
| US3010877A (en) * | 1959-09-03 | 1961-11-28 | American Cyanamid Co | Method of preparing 15-hydroxy pregnenes |
| JP2591640B2 (en) * | 1988-02-04 | 1997-03-19 | 帝国臓器製薬株式会社 | Novel 2-oxapregnane compound |
| JP2591640Y2 (en) | 1993-05-13 | 1999-03-10 | 株式会社吉野工業所 | Liquid storage bag |
| US6046185A (en) | 1996-07-11 | 2000-04-04 | Inflazyme Pharmaceuticals Ltd. | 6,7-oxygenated steroids and uses related thereto |
| CN100368425C (en) * | 1996-07-11 | 2008-02-13 | 茵弗莱采姆药物有限公司 | 6,7-oxidized steroids and uses thereof |
-
2017
- 2017-02-10 JP JP2017023569A patent/JP6892278B2/en active Active
-
2018
- 2018-02-08 WO PCT/JP2018/004295 patent/WO2018147345A1/en not_active Ceased
- 2018-02-08 MX MX2019009560A patent/MX389873B/en unknown
- 2018-02-08 US US16/481,970 patent/US10815268B2/en active Active
- 2018-02-08 CN CN201880011073.7A patent/CN110267967B/en active Active
- 2018-02-08 IL IL268584A patent/IL268584B2/en unknown
- 2018-02-08 KR KR1020197024864A patent/KR102467727B1/en active Active
- 2018-02-08 ES ES18752066T patent/ES2968278T3/en active Active
- 2018-02-08 EP EP18752066.3A patent/EP3581577B1/en active Active
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| US20190389900A1 (en) | 2019-12-26 |
| MX389873B (en) | 2025-03-11 |
| MX2019009560A (en) | 2019-10-15 |
| EP3581577A1 (en) | 2019-12-18 |
| CA3049753A1 (en) | 2018-08-16 |
| EP3581577A4 (en) | 2020-12-30 |
| CN110267967A (en) | 2019-09-20 |
| JP6892278B2 (en) | 2021-06-23 |
| IL268584A (en) | 2019-09-26 |
| IL268584B1 (en) | 2023-08-01 |
| EP3581577B1 (en) | 2023-10-11 |
| CN110267967B (en) | 2022-07-19 |
| WO2018147345A1 (en) | 2018-08-16 |
| KR20190116986A (en) | 2019-10-15 |
| JP2018127434A (en) | 2018-08-16 |
| KR102467727B1 (en) | 2022-11-15 |
| ES2968278T3 (en) | 2024-05-08 |
| BR112019016361A2 (en) | 2020-04-07 |
| US10815268B2 (en) | 2020-10-27 |
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